Enhancement of lipopolysaccharide-induced tumor necrosis factor production in mice by carrageenan pretreatment

Abstract

Tumor necrosis factor (TNF) is a cytokine which mediates endotoxin shock and causes multiple organ damage. It is thought that macrophage (MP) activation is necessary to increase lipopolysaccharide (LPS)-induced TNF production and lethality. Carrageenan (CAR) is sulfated polygalactose which destroys MP; it is used as a MP blocker. We found that CAR pretreatment can increase both endotoxin-induced TNF production and the mortality rate in mice. The ddY mice (7 to 8 weeks old) were injected intraperitoneally with CAR (5-mg dose) and challenged intravenously with LPS 24 h later. Without CAR pretreatment, LPS doses of less than 10 micrograms did not induce TNF in sera. After pretreatment, however, about 3 x 10(3) to 4 x 10(4) U of TNF per ml was produced after LPS injection at doses of 0.1 to 10 micrograms, respectively. TNF production was significantly increased by CAR pretreatment at LPS doses of more than 10 micrograms. CAR pretreatment rendered the mice more sensitive to the lethal effect of LPS; 50% lethal doses of LPS in CAR-pretreated mice and nonpretreated mice were 26.9 and 227 micrograms, respectively. The mortality of the two groups was significantly different at doses of 50, 100, and 200 micrograms of LPS. CAR increased LPS-induced TNF production and mortality within 2 h, much earlier than MP activators, which needed at least 4 days. Our results made clear that TNF production is enhanced not only by a MP activator but also by a MP blocker.